Zinc-Mediated Mannich-Type Reaction of 2,2,2-Trifluorodiazoethane with Imines: Access to β-CF3-Amines

Article abstract of DOI:10.1021/acs.orglett.8b02816

A zinc-mediated Mannich-type transformation of 2,2,2-trifluorodiazoethane with a series of imines has been described. This method provides facile access to a wide range of trifluorodiazoethyl-substituted amines in moderate to high yields under mild conditions. The synthetic utility of the afforded adducts is demonstrated by further transformations to valuable β-CF₃-amines.

Full text of DOI:10.1021/acs.orglett.8b02816

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Zinc-Mediated Mannich-Type Reaction of 2,2,2-Trifluorodiazoethane
with Imines: Access to β‑CF3‑Amines
Ran Guo,§,† Ning Lv,§,† Fa-Guang Zhang,*,† and Jun-An Ma*,†,‡
†Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation
Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072, P.R. China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P.R. China
S
* Supporting Information
ABSTRACT: A zinc-mediated Mannich-type transformation of 2,2,2-trifluorodiazoethane with a series of imines has been
described. This method provides facile access to a wide range of trifluorodiazoethyl-substituted amines in moderate to high
yields under mild conditions. The synthetic utility of the afforded adducts is demonstrated by further transformations to
valuable β-CF3-amines.
F3-containing amines represent a type of useful structural
motif that has been frequently found in pharmaceuticals,
tendency of β-elimination with fluoride.5 One of the key
factors that could increase the stability of the α-trifluoromethyl
organometallic species is the degree of covalency in a bond
between the carbon and metal.6 In this context, we envisioned
that 2,2,2-trifluorodiazoethane (CF3CHN2),7 which has a
diazo moiety as a potential stabilizing group, could serve as a
suitable masked trifluoroethyl nucleophile after treatment with
an organometallic base.8 To our delight, in the presence of
dimethylzinc, a Mannich-type transformation of 2,2,2-trifluor-
odiazoethane with a series of imines smoothly underwent a
reaction to afford trifluorodiazoethyl-substituted amines with
moderate to high yields under mild conditions (Scheme 1c).9
After removal of the diazo moiety in the adducts, the expected
β-CF3-amines were generated in high yield, illustrating the
successful development of CF3CHN2 as a masked trifluor-
oethyl nucleophile. Meanwhile, the diazo adducts could also be
readily converted to trifluoromethyl ketal and alcohol by
simple synthetic manipulations. Moreover, the preparation of
the CF3-containing analogue of the drug idelalisib has also
been accomplished by using this protocol as a key step.10
Hence, as a part of our continued interest in the chemistry of
trifluorodiazoethane,11 herein, we report our results on this
project.12
C
agrochemicals, and bioorganic applications.1 In the past two
decades, great advances have been achieved in Mannich-type
nucleophilic trifluoromethylation of imines, which has been
recognized as a convergent and efficient manner to access α-
CF3 amines (Scheme 1a).2 In sharp contrast, the analogous
Scheme 1. Preparation of α-CF3-Amines and β-CF3-Amines
from Imines via Mannich-Type Reactions
We started our investigation by choosing N-diphenylphos-
phinyl imine 1a as the model substrate. Pleasingly, the target
product 2a was obtained in 88% yield when dimethylzinc was
employed as the base in THF at −20 °C (Table 1, entry 1).
Subsequently, several different organometallic bases (dieth-
ylzinc, n-butyllithium, and ethylmagnesium bromide) were
evaluated, providing traces or much lower yields of desired
approach, named direct nucleophilic trifluoroethylation of
imines to β-CF3-amines, has not been reported, to the best of
our knowledge (Scheme 1b).3 Indeed, this is a very challenging
transformation owing to the difficult availability and poor
stability of the trifluoroethyl nucleophiles.4 It has been
demonstrated that trifluoroethyl nucleophiles such as α-
trifluoromethyl carbanions and their corresponding organo-
metallic species are prone to decompose because of their high
Received: September 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02816
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Letter
a
reaction, and no generation of 2a was observed in both cases
(entries 5 and 6).13 These results reveal that this trans-
formation is very sensitive to the base used in the
deprotonation step. Subsequently, a survey of different solvents
was conducted, and we found that comparable yields were
achieved in acetonitrile and DMF (entries 7−9). Finally, after a
screen of other reaction parameters including temperature and
reaction time (entries 10−13), the best reaction conditions of
this Mannich-type transformation were established to be in
THF at −20 °C for 12 h using dimethylzinc as the base (entry
1). Furthermore, gram-scale reaction was also conducted and
smoothly produced 2a in 81% yield (entry 14). In addition,
control experiments with deuterium oxide were performed, and
the deutered trifluorodiazoethane was detected. These results
suggest that the zinc reagent could be employed as a base to
deprotonate the diazo substrate.14
With the optimized reaction conditions in hand, we then set
out to probe the substrate scope with a broad array of imines.
These results are summarized in Scheme 2. For aromatic
diphenylphosphinyl imines, regardless of the substituent’s
positions on the phenyl ring (para, ortho, and meta) or its
electronic nature (electron-neutral, electron-donating, or
electron-withdrawing), the desired trifluorodiazoethyl-substi-
tuted amines could be obtained smoothly in good to high
yields (Scheme 2, products 2b−q). 1-Naphthyl-, 2-naphthyl-,
2-furanyl-, and 2-thienyl-substituted imines were also found to
be good substrates, thus generating the desired products 2r−u
in high yields. Remarkably, this method also tolerates
Table 1. Optimization of Reaction Conditions
b
entry
solvent
base
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
CH3CN
DMF
toluene
THF
THF
THF
THF
THF
Me2Zn
Et2Zn
n-BuLi
EtMgBr
Cs2CO3
DBU
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
−20
−20
−20
−20
25
88
68
15
trace
0
25
0
−20
−20
−20
−20
−10
−30
30
78
72
0
73
63
80
trace
81
c
10
11
12
13
d
14
−20
a
General reaction conditions: 1a (0.5 mmol), CF3CHN2 (1.5 mmol),
and base (1.0 mmol) in solvent (3 mL) at the given temperature for
12 h. Isolated yield. CF3CHN2 (1.0 mmol). 3 mmol scale of imine
b
c
d
1a.
product 2a (entries 2−4). Then, one inorganic base (Cs2CO3)
and one organic base (DBU) were also examined in this
Scheme 2. Substrate Scope of Mannich-Type Reaction between CF3CHN2 and Imines
B
DOI: 10.1021/acs.orglett.8b02816
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cinnamyl- and phenylethynyl-derived imines and led to the
formation of 2v and 2w, albeit with slightly decreasing yields. It
is worth noting that several alkyl-substituted imines, even those
including the bulky tert-butyl substitutent, are also compatible
with this transformation, thus delivering corresponding
adducts 2x−a′ in good to high yields. Moreover, two sulfonyl
group protected cyclic imines also proved to be viable
substrates and generated 2b′ and 2c′ in 81% and 71% yields,
respectively. It should be noted that 2c′ was formed from a
ketimine substrate, which further demonstrates the broad
substrate scope of this transformation. In addition, both tert-
butyloxycarbonyl (Boc)- and toluenesulfonyl (Ts)-derived
imines have also been evaluated in this reaction. In these
two cases, corresponding adducts 2d′ and 2e′ were obtained
smoothly in 70% and 78% yields, respectively.
To further demonstrate the synthetic utility of this method
toward biologically active targets, we then became interested in
the preparation of a β-CF3-amine-containing drug analogoue.
Idelalisib, which is a drug used for the treatment of certain
hematological malignancies, became our selection, as its CF3-
substitued analogoue has been demonstrated to be a drug
candidate for the treatment of diseases related to PI3K
enzymes.10 As outlined in Scheme 4, the imine precursor 9 was
Scheme 4. Preparation of CF3-Containing Analogue of Drug
Idelalisib
Subsequently, several synthetic elaborations of trifluorodia-
zoethyl-substituted amines have been implemented. As shown
in Scheme 3a, the diazo moiety of compound 2a was removed
Scheme 3. Further Transformations of Mannich Adducts to
β-CF3 Amines
prepared in practical yield by condensation of diphenylphos-
phinamide with aldehyde 8 which was synthesized within 4
steps from 2-amino-5-fluorobenzoic acid 7 (see the Supporting
Information for details).17 Subsequently, the Mannich-type
reaction of 9 with CF3CHN2 was conducted smoothly to give
the addition product 10 in 88% yield. Then, the target
trifluoroethylated molecular 11 was obtained in 83% yield via
an identical unmasked operation. This β-CF3-amine com-
pound holds promise for the downstream synthesis of CF3−
idelalisib according to the literature.10 The successful
preparation of CF3−idelalisib further demonstrates that our
method can be employed as a complementary and expedient
approach to access relevant targets bearing a β-CF3-amino
moiety.
In summary, we have developed a zinc-mediated Mannich-
type reaction of CF3CHN2 to imines under mild conditions.
This protocol provides efficient access to a wide range of
trifluorodiazoethyl-substituted amines in moderate to high
yields. Notably, the obtained adducts were readily converted to
β-CF3-amines, which shows the feasibility of utilizing
CF3CHN2 as a masked nucleophilic trifluoroethylating reagent.
Further studies, including an expansion of the substrate scope
as well as an enantioselective version and mechanistic
investigations, are underway in our laboratory and will be
reported in due course.
by treatment with Pd/C under a hydrogen atmosphere,
thereby leading to the corresponding product 3a in high yield.
It is noteworthy that this compound is exactly the
aforementioned nucleophilic trifluoroethylated product of
imine, thus verifying the feasibility of our proposal. This
transformation also tolerates substrates with an electron-
donating group, electron-withdrawing group, and 2-furanyl
group, thereby leading to the formation of compounds 3b−d
in decent yields. Also, the β-CF3-amine 4 was obtained
smoothly by a simple deprotection procedure (Scheme 3b).
Next, trifluoromethyl ketal 5 was afforded with 92% yield when
oxone was employed for the oxidation of 2a (Scheme 3c). This
compound could be readily converted into α-CF3-β-amino
alcohol 6 in high yield as a single diastereoisomer.15 This kind
of β-amino alcohol holds promise for the preparation of
peptidomimetics and other biologically active fluorinated
compounds.16
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02816.
Experimental details and spectral data of all new
compounds (PDF)
C
DOI: 10.1021/acs.orglett.8b02816
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: majun_an68@tju.edu.cn.
*E-mail: zhangfg1987@tju.edu.cn.
ORCID
Fa-Guang Zhang: 0000-0002-0251-0456
Jun-An Ma: 0000-0002-3902-6799
Author Contributions
§R.G. and N.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21472137, 21532008, and
21772142) and the National Basic Research Program of
China (973 Program, 2014CB745100).
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DOI: 10.1021/acs.orglett.8b02816
Org. Lett. XXXX, XXX, XXX−XXX